Additional Chromosomal Abnormalities in Philadelphia Chromosome-Negative Metaphases Appearing during Therapy with Imatinib, Dasatinib, Nilotinib and Ponatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1577-1577 ◽  
Author(s):  
Ghayas C. Issa ◽  
Hagop M. Kantarjian ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Clinical Outcomes ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Banding Technique ◽  
First Year ◽  
Additional Chromosomal Abnormalities

Abstract Background Additional chromosomal abnormalities (ACAs) in the Philadelphia chromosome (Ph)-negative metaphases that emerge as patients with chronic myeloid leukemia (CML) are treated with tyrosine kinase inhibitors (TKIs) have been reported during treatment with imatinib. It has been suggested that these might be associated with an inferior outcome and in rare instances lead to the emergence of a new malignant clone resulting in myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) (Jabbour et. al, Blood 2007). This phenomenon has not been well characterized when other TKIs are used. We conducted a retrospective analysis of patients treated on imatinib, dasatinib, nilotinib, and ponatinib frontline trials to assess the frequency and prognostic impact of ACAs appearing during the treatment after achieving cytogenetic response. Patients and Methods A total of 524 patients with CML were evaluated with a median age at diagnosis of 48 years (range 15 to 86). These included 236 patients treated with imatinib, 125 with nilotinib, 118 with dasatinib and 45 with ponatinib. All the patients were treated in clinical trials approved by the institutional board review and signed an informed consent in accordance with institutional guidelines and in accordance with the declaration of Helsenki. Conventional cytogenetic analysis was done in bone marrow cells using standard G-banding technique at baseline, every 3 months during the first year, then every 6-12 months. Clonal ACAs were identified as abnormalities present in ≥2/20 metaphases or, if only one metaphase, present in ≥2 consecutive assessments. Results After a median follow-up of 83.8 months (range 0.3-176.6 months) 13% (72/524) patients had ACAs, of which 7% (41/524) were clonal. ACAs were seen in 11% (27/236) of patients on imatinib compared to 11% (13/118, p=0.9) on dasatinib, 19 % (24/125, p= 0.04) on nilotinib, and 17% (8/45, p=0.2) on ponatinib. Six patients had both clonal evolution (CE) and ACAs at different times. The median number of metaphases containing ACAs was 5/20 (range 1 to 20) with an average of 7/20. Most appeared within the first year of the start of the TKI (median 6 months, range 3-72 months); they first appeared after 12 months of therapy in 21 of the 72 (29%) patients. ACAs were transient and were detected in 2 or less time points in 52 of the 72 (72%) cases. The most common clonal ACAs were - Y (13/41) and +8 (4/41). The rates of cytogenetic and molecular responses were similar for patients with and without clonal ACAs (CCyR: 88% vs 91%; p=0.55) (MMR: 78% vs 86%, p=0.20). Having clonal ACAs did not affect the rate of deep molecular response either (MR4.5 71% vs 67%; p =0.65). There was no significant difference in EFS and OS (5y EFS 73% vs 86%; p=0.19) (5y OS 77% vs 93%; p=0.06) although there was a trend for lower rates for both. Responses and clinical outcomes were similar between different TKIs for patients with and without clonal ACAs. One patient with -7 treated with ponatinib developed MDS. Monosomy 7 appeared 9 months from the start of treatment in 9/20 metaphases and persisted. He was taken off ponatinib because of pancytopenia. He subsequently received bosutinib, achieved and maintained a CCyR. A high-risk MDS was documented approximately 1 year after appearance of the -7 clone. He was started on decitabine and achieved a partial cytogenetic response for MDS. Another patient in the imatinib cohort with -7 developed secondary AML (CCyR for CML) and died from a multiple organ failure after allogeneic stem cell transplant from a one antigen-mismatched unrelated donor. There was a third patient with -7 that later had CE and developed Ph+ CML blast phase. Conclusion ACAs are rare and mostly transient events that appear during the treatment of CML with TKIs. These changes do not affect responses or clinical outcomes, independent of what TKI is used. A small subset of patients with -7 may develop AML or MDS warranting close monitoring of patients with changes that are reminiscent of those diseases. Molecular analysis after appearance of ACAs could help identify mutations driving the Ph-clone into AML or MDS. Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

Studying the Impact of Imatinib Mesylate (IM) Adherence in Chronic Myeloid Leukemia (CML) patients’ Responses in the State of Qatar

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5537-5537
Author(s):  
Nader I Al-Dewik ◽  
Hisham Morsi ◽  
Rola Ghasoub ◽  
Mohamed A. Yassin
Keyword(s):  
Risk Factors ◽  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Monitoring System ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Patient Adherence ◽  
Poor Adherence ◽  
Additional Chromosomal Abnormalities

Abstract Background: The introduction of Imatinib Mesylate (IM) has revolutionized the outcome of Chronic Myeloid Leukemia (CML) patients. However, the success of the rationally designed therapy is tempered by the understanding that a substantial proportion of CML patients fail treatment. In Qatar, 54% of CML patients do fail IM according to European leukemia net (ELN) recommendations 2013. Point mutation & unique tri-nucleotide insertions explained only 14% of treatment failure. Additional chromosomal abnormalities were the most common cause of IM failure in our patients’ cohort & were documented in 50% of cases. 14% of patients stopped IM due to intolerance & the mechanisms of resistance remained unknown in 28% of patients. Other cause such as patients’ adherence to IM is being prospectively investigated. Therefore, Non adherence to IM must be ruled out as a possible cause of lack of optimal response before considering such patients to be IM-resistant & switching them to next-line treatment. Aim: To correlate between CML patients’ adherence to IM treatment & their responses and identify the factors affecting non-adherence. Methods: 36 CML patients (5 citizens & 31 residents) are consented into the study. adherence to Imatinib was assessed using four different techniques: calculation of the Medication Possession Ratio (MPR), electronic Medical Records (eMR), survey questionnaire & Medication Event Monitoring System (MEMS). MPR is defined as the sum of the days' supply of medication divided by the number of days between the first fill & the last refill. Patients medications history was obtained from questionnaire, pharmacy electronic Medical record (eMR) & studying drug – drug interactions was done using MICROMEDEX® 1.0 (Healthcare Series). The Questionnaire used to identify potential factors revolving around the patient's lifestyle, affordability & knowledge related to IM, in addition to standardized evaluation based on the 9-item Morisky Medication Adherence Scale (MMAS) ranging from 1 to 13. Scores ≤10 indicates non adherence whereas ≥ 11 indicates adherence. Patient adherence was tracked electronically using the Medication Electronic Monitoring System (MEMS) that provided real time measures of adherence for a period up to 4 months. 95 Peripheral blood (PB) samples were collected & the level of BCR-ABL1 transcripts was measured via RT-QPCR. The ELN 2013 recommendations for the management of CML was adopted & employed in this study to assess the response/resistance of patients to treatment. Responses were defined at the haematological, cytogenetic & molecular levels. Patients responses were classified into optimal, suboptimal or failure. Results: Out of 36 patients, 23 patients were adherent (MMAS, MPR &MEMS were ≥ 80%) & 13 patients were classified as non-adherent (MMAS, MPR &MEMS were <80 % ) All adherent patients were optimally responded to the treatment (achieved CCyR & MMR) while the 13 non-adherent patients failed the treatment (2 patients were intolerant, 9 patients did not achieved CCyR & molecular response & 2 patients developed additional chromosomal abnormalities. Questionnaire feedback results showed that 69% patients could not afford to pay the remaining 10% of its cost, the other factors such as lack of knowledge (comprehensive & insight of illness) & illiteracy were observed in 35% & 30% of patients respectively. Discussion & conclusion: Due to high rate of Imatinib failure in Qatar, patient’s adherence to treatment was studied. Non adherence to the treatment was one of the most common causes of Imatinib failure in our patients’ cohort & was documented in 36% of cases. Economic factor (Unaffordable drug price) was one of the main causes of non-adherence & efforts should be made locally to improve access to medications for cancer diseases. Other risk factors associated with poor adherence can be improved by close monitoring & dose adjustment. Monitoring risk factors for poor adherence in combination with patient education that includes direct communication between the health care teams doctors, nurses pharmacists & patients are essential components for maximizing the benefits of TKI therapy & could rectify this problem. Our preliminary results showed that patients’ response to treatment may be directly linked to patient adherence to the treatment. However, further in-depth & specific analysis may be necessary in a larger cohort. Disclosures Al-Dewik: Hamad Medical Corporation (HMC): Employment, HMC Medical Director's Grant Competition (GC) 1013A Patents & Royalties, Research Funding. Morsi:HMC: Employment, Research Funding. Ghasoub:HMC: Employment, Research Funding.

scholarly journals Additional chromosomal abnormalities in Philadelphia positive chronic myeloid leukemia

2019 ◽  
Vol 36 (2) ◽  
Author(s):  
Sunila Tashfeen Arif ◽  
Rafia Mahmood ◽  
Saleem Ahmed Khan ◽  
Tahir Khadim
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cytogenetic Analysis ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Newly Diagnosed ◽  
Cytogenetic Abnormalities ◽  
Conventional Cytogenetic Analysis ◽  
Major Route ◽  
Additional Chromosomal Abnormalities

Objective: To determine the frequency of additional chromosomal abnormalities in Philadelphia chromosome positive Chronic Myeloid Leukemia (CML) by conventional cytogenetic analysis. Methods: This descriptive cross sectional study was conducted at Armed Forces Institute of Pathology (AFIP), Rawalpindi, from January 2012 to December 2016. A total number of 528 newly diagnosed CML patients were included in the study. The subjects were tested for the presence of Philadelphia (Ph) chromosome and other additional cytogenetic abnormalities by conventional cytogenetic analysis interpreted according to International System of Human Cytogenetic Nomenclature (ISCN) criteria. Molecular analysis for BCR-ABL was also performed for each patient. The additional cytogenetic abnormalities were then classified into major route abnormalities and minor route abnormalities. Results: Out of the 528 newly diagnosed CML patients, 378 (71.6%) were males and 150 (28.4%) were females. The age of patients ranged between 18 to 74 years. Four hundred and ninety-eight (94.3%) patients showed Philadelphia chromosome on karyotyping while 30 (5.7%) were negative for the Philadelphia chromosome. On analysis of these 498 Philadelphia positive patients, additional cytogenetic aberrations were detected in 26 (4.9%) patients. Of these, 7 (1.3%) had major route abnormalities while 19 (3.6%) had minor route abnormalities. Conclusion: The frequency of additional chromosomal abnormalities in our study were not in accordance with previous local and international studies. doi: https://doi.org/10.12669/pjms.36.2.1384 How to cite this:Tashfeen S, Mahmood R, Khan SA, Khadim T. Additional chromosomal abnormalities in Philadelphia positive chronic myeloid leukemia. Pak J Med Sci. 2020;36(2):---------. doi: https://doi.org/10.12669/pjms.36.2.1384 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Clinical Significance of Additional Chromosomal Abnormalities In Ph-Positive and Ph-Negative Cells In Patients with Chronic Myeloid Leukemia Treated by Tyrosine Kinase Inhibitors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1683-1683
Author(s):  
Anna G. Turkina ◽  
Olga Vinogradova ◽  
Alexandra Vorontsova ◽  
Ekaterina Chelysheva ◽  
Olga Lazareva ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Chromosomal Abnormalities ◽  
Cytogenetic Response ◽  
2Nd Generation ◽  
Risk Of Progression ◽  
Variant Chromosome ◽  
Additional Chromosomal Abnormalities

Abstract Abstract 1683 Introduction. Additional chromosomal abnormalities (ACA) in Ph'-positive (Ph'+) cells firstly described more than 30 years ago were associated with progression of chronic myeloid leukemia (CML) and often were founded in advanced stages of the disease. Prognostic significance of ACA in Ph'+ cells in the era of tyrosine kinase inhibitors (TKI) are not yet fully clarified. The ACA in Ph'-negative (Ph'-) cells seem to have no adverse prognostic impact, but it is not possible to exclude the development of myelodisplasia within the long lasting persistence of such clones. Long-term cytogenetic monitoring can better understand the biological aspects of CML. Aim. To estimate the clinical significance of ACA in Ph'+ and Ph'- cells in CML patients (pts) treated by TKI 1st and 2nd generation (TKI-1 or 2). Materials and methods. The complete peripheral blood count, morphological and cytogenetic examination of bone marrow (BM) cells have been done for 435 CML pts in different disease stages: chronic phase (CP)/accelerated phase (AP)/blast crisis (BC) pts were 336/78/21 respectively. The median (Me) age was 50 years (y) (16–61), Me follow-up- 97 months (mo) (5−265). Results and discussion. The ACA in Ph'+ cells were revealed by conventional cytogenetic study generally in 50 (11,5%) of 435 CML pts. ACA in Ph'+ cells were a rare event for CP and AP: 9% and 14% of pts respectively and more frequent for BC: 43% of pts. The most frequent ACA was the additional Ph'-chromosome (addPh'+) found in 50% of cases. 17pts had addPh'+ alone, while 13pts had also other ACA: trisomy 8 (8 cases), deletion or monosomy 7 (3 cases) and complex abnormalities (2 cases in CP & AP); dominated by male (M: F=23: 7). The duration of IM treatment in 16pts with addPh'+ was from 6mo to 5,5y. The follow-up duration of pts with addPh'+ was from 26 to 176 mo (Me 107 mo). All 16 pts have achieved complete hematological response (CHR) after 3 to 6mo of Imatinib (IM) treatment, but all pts with standard IM doses had primary cytogenetic resistance. Complete cytogenetic response (CCyR) was achieved in 56%pts without ACA, in 24% with ACA, and only in 7% with addPh'+. Due to IM resistance, 14 pts were switched to TKI-2 (Dasatinib – 10pts, Nilotinib – 3pts, Bosutinib – 1pt); 3 of these pts later progressed to AP; for 2 of them T315I mutation was found. All of the 11 pts still in CP have achieved CHR; partial cytogenetic response was founded in 45% and CCyR in 36% cases. At present, 43% pts with ACA died: 11% in CP, 82% in AP and all in BC. The 8-year overall survival (OS) for CML CP pts with ACA was 83%, no statistically significant (p>0,5) difference with the general CML CP pts group, treated by TKI. The assessment by multifactorial Cox model with variable risk factors revealed the increased probability of fatal outcome in CML CP more than 16 times higher in pts with ACA vs. patients without ACA. The variant chromosome abnormalities were rare: 13pts (3 %), but in 77% of them there was cytogenetic resistance pts and high risk of progression. ACA in Ph'- cells were founded in 13 (3%) pts only after the achievement of major cytogenetic response. 10 of them received IM 600–800mg daily; 3pts received 2nd generation of TKI. All those patients got the MCR only after 18–36 mo of treatment and 11 (85%) of 13pts achieved the CCyR. Ph'- clone was constantly founded only in 1 patient, in all other cases it was not constant but persisted from one analyses to other. No myelodisplastic changes were founded in the BM of 5 examined pts after IM treatment within 3–7y. All pts with ACA in Ph'- cells are alive. Conclusion. The durable persistence of Ph'+ cells in CML CP pts is a marker of therapy resistance but not all cases are associated with disease progression. The addPh'+ during IM treatment was associated with cytogenetic resistance. The dose escalation of IM was ineffective in the majority of cases, only TKI-2 therapy could restore Ph'- neg. hematopoiesis and suppressed addPh'+ clone more effectively. This finding should be tested in large-scale studies. The male predominance in pts with addPh'+ also needs further investigation. In contrast to other reported data, we founded that the prognosis for 77% of pts with the variant chromosome abnormalities was poor and associated with cytogenetic resistance and high risk of progression on TKI-1 and 2 therapy. In most pts with ACA in Ph'- cells a dose escalation of IM and switching to TKI-2 was needed but generally the disease prognosis was favorable. Disclosures: Turkina: Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Vinogradova:Novartis: Research Funding, Speakers Bureau; Bristol: Speakers Bureau. Chelysheva:Novartis: CML registry, Research Funding, Speakers Bureau; Bristol: Speakers Bureau. Lazareva:Novartis: CML registry, Research Funding, Speakers Bureau. Gusarova:Novartis: Honoraria, Speakers Bureau. Khoroshko:Novartis: Speakers Bureau; Bristol: Speakers Bureau.

Additional Cytogenetic Abnormalities and/or Philadelphia Chromosome Metaphase Mosaicism Might Adversely Influence Survival and Imatinib Response in Chronic Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4783-4783
Author(s):  
Andrew P. Landstrom ◽  
Rhett P. Ketterling ◽  
Ryan A. Knudson ◽  
Gordon W. Dewald ◽  
Ayalew Tefferi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Philadelphia Chromosome ◽  
Median Length ◽  
Cytogenetic Abnormalities ◽  
Kaplan Meier ◽  
Ph Chromosome ◽  
Cytogenetic Remission ◽  
Additional Chromosomal Abnormalities

Abstract Background: Chronic myeloid leukemia (CML) is invariably associated with the reciprocal translocation of BCR and ABL to form the Philadelphia chromosome (Ph), t(9;22)(q34;q11). At diagnosis, a small proportion of patients display additional cytogenetic abnormalities and/or a variable proportion of cytogenetically normal metaphases that coexist with Ph-positive metaphases. The objective of the current study was to examine the prognostic relevance of these two scenarios. Methods: The study population consisted of 65 (47.7% female) consecutive, newly diagnosed CML patients seen at the Mayo Clinic with a median age of 59 years. 44.5 percent were initially treated with interferon alpha (IFN) resulting in complete cytogenetic remission in 10.7 percent for a median length of 5.83 years, partial cytogenetic remission in 3.57 percent for a median length of 2 years. 55.5 percent were treated with imatinib (Gleevec) resulting in complete cytogenetic remission in 54.1 percent for a median length of 3.08 years, partial cytogenetic remission in 13.5% for a median length of 1.08 years. Results: Survival at five years through Kaplan-Meier analysis was approximately 92 percent in patients demonstrating only the Ph chromosome (n = 53), versus 60 percent in patients with additional chromosomal abnormalities (n = 12; p &lt; 0.0001 by both Logrank and Breslow-Gehan-Wilcox analysis). Furthermore, patients with additional chromosomal abnormalities demonstrated lower rates of either complete or partial cytogenetic remission with imatinib therapy. Similarly, five year survival of patients with less than 90% Ph-positive metaphases at diagnosis (n = 4) was approximately 60% compared to 92% in patients with greater than 90% Ph-positive metaphases (n = 61; p = 0.01 by Logrank and p = 0.001 by Breslow-Gehan-Wilcox analysis). Additionally, the former group of patients was significantly less responsive to imatinib. Finally, there was significant correlation between Ph-positive metaphase mosaicism and the presence of additional chromosomal abnormalities (p = 0.05). Conclusion: Although it is tempting to speculate the possibility that Ph-chromosome mosaicism and/or additional cytogenetic abnormalities at presentation of CML is a surrogate for the presence of Ph-negative imatinib-resistant clones, the preliminary results from the current study require validation from a larger study. Figure Figure Figure Figure

scholarly journals Chromosomal Aberrations in Chronic Myeloid Leukemia: Response to Conventional TKIs and Risk of Blastic Transformation

2021 ◽  
Vol 6 (1) ◽  
pp. 35-39
Author(s):  
Shafaq Maqsood ◽  
Fatima Ali ◽  
Abdul Hameed ◽  
Neelam Siddiqui
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chromosomal Abnormalities ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Trisomy 8 ◽  
Additional Chromosomal Abnormalities

Background and Purpose: Chronic Myeloid Leukemia (CML) is a common hematological malignancy. The characteristic molecular abnormality is the presence of Philadelphia chromosome or BCR-ABL fusion gene which is the result of 9:22 translocation. Tyrosine kinase inhibitors (TKIs) form the main stay of treatment in CML with excellent responses. The purpose of this study was to determine the impact of additional chromosomal abnormalities on outcomes in CML.Methods: This is a retrospective chart review of all patients who were diagnosed with CML in chronic phase (CP) with additional chromosomal abnormalities (ACAs) over a period of 5 years from 2010 to 2015 at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. Results: A total of 283 patients were diagnosed with CML from January 2010 to January 2015. 31 patients out of these were found to have additional chromosomal abnormalities at the time of diagnosis in addition to BCR-ABL fusion gene or Philadelphia chromosome detection. Out of these 31 patients, 23 (74.2%) were males whereas 8 (25.8%) were females. 13 (41.9%) were in the age group of 31 to 50 years whereas the other two groups that is 18 to 30 years and 51 to 70 years had 9 patients each. After approval from the government which usually takes a standard 2-3 weeks’ time, these patients were started on tyrosine kinase inhibitors which was Imatinib in 30 (96.8%) and Nilotinib in 1 (3.2%) patient. Conventional cytogenetic analysis performed for each patient at the time of diagnosis revealed that 11 (35.5%) of patients had variant Philadelphia chromosome followed by 7 patients (22.6%) with trisomy 8. 5 patients (16.1%) had multiple chromosomal abnormalities including trisomy 8, deletion 1 and isochrome 17q. 2 patents each had isochrome 17q, inversion 3 and deletion 9 abnormalities. 1 patient had deletion 7 whereas 1 had variant Philadelphia chromosome with other chromosomal abnormalities. Conclusion: It was evident that frequently occurring ACAs In our CML population were Variant Philadelphia chromosome and trisomy 8.

THE CASE VARIANT TRANSLOCATION T(3;9;22)(P24;Q34;Q11) IN CHRONIC MYELOID LEUKEMIA

2018 ◽  
Vol 64 (6) ◽  
pp. 810-814
Author(s):  
Kodirzhon Boboev ◽  
Yuliana Assesorova ◽  
Kh. Karimov ◽  
B. Allanazarova
Keyword(s):  
Adverse Effect ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Genetic Locus ◽  
Philadelphia Chromosome ◽  
Chromosome 9 ◽  
Banding Technique ◽  
Variant Translocation

This paper presents a case of chronic myeloid leukemia with an earlier unknown variant translocation t (3; 9; 22) (p24; q34; q11) detected by cytogenetic research using the GTG-banding technique. Despite the absence of the classical Philadelphia chromosome, the presence of chromosome 9 and 22 derivatives, as well as the BCR-ABL fusion gene, allow this translocation to be considered pathogenetic for CML. A good response of the patient to the treatment with glivec is that there is no adverse effect on the pathogenesis of the disease of an additional genetic locus (3p24) involved in complex restructuring.

A randomized study of interferon-α versus interferon-α and low-dose arabinosyl cytosine in chronic myeloid leukemia

Blood ◽  
2002 ◽  
Vol 99 (5) ◽  
pp. 1527-1535 ◽  
Author(s):  
Michele Baccarani ◽  
Gianantonio Rosti ◽  
Antonio de Vivo ◽  
Francesca Bonifazi ◽  
Domenico Russo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Low Dose ◽  
Response Rate ◽  
Randomized Study ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Arabinosyl Cytosine

Interferon-α (IFN-α) has significantly prolonged survival in chronic myeloid leukemia (CML), but some patients do not respond and many responses are not durable. To improve the results, IFN-α has been combined with other treatments, but so far only the association with low-dose arabinosyl cytosine (LDAC) has been shown to increase the response rate and to prolong survival. Here are reported the results of a study of 538 Philadelphia chromosome–positive CML patients who were assigned at random to treatment with IFN-α2a alone or in combination with LDAC. The scheduled dose of IFN-α2a was 56IU/m2/d. The scheduled dose of AC was 40 mg/d for the first 10 days of each month of treatment. The efficacy endpoints were a complete hematologic response rate at 6 months (62% in the IFN-α–plus–LDAC arm versus 55% in the IFN-α arm; P = .11), major cytogenetic response (MCgR) rate at 24 months (28% versus 18%; P = .003), and overall survival (5-year survival, 68% versus 65%; P = .77). Treatment did not affect overall survival within different prognostic risk groups: low, intermediate, or high. Also the duration of MCgR was identical. The results of this study confirm the results of a similar French study only for the response rate, not for survival, suggesting that the relationship between cytogenetic response and survival may be extremely variable and that a meta-analysis of these and other studies of IFN-α versus IFN-α plus LDAC is required to settle the issue of the role of LDAC in the treatment of CML.

Bosutinib As Therapy for Chronic Phase Chronic Myeloid Leukemia Following Failure with Imatinib Plus Dasatinib and/or Nilotinib: 24-Month Minimum Follow-up Update

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3785-3785 ◽  
Author(s):  
H. Jean Khoury ◽  
Carlo Gambacorti-Passerini ◽  
Hagop M. Kantarjian ◽  
Dong-Wook Kim ◽  
David Marin ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Grade 3

Abstract Abstract 3785 Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure. A total of 119 pts aged ≥18 y with prior imatinib (IM) failure plus dasatinib (DAS) resistance (n = 38), DAS intolerance (n = 50), nilotinib (NIL) resistance (n = 27), NIL intolerance (n = 1), or failure of DAS and NIL (n = 3) received BOS starting at 500 mg/d. Median age was 56 y (range, 20–79 y); 45% of pts were male; median time from CML diagnosis was 6.5 y (range, 0.6–18.3 y). Median BOS duration was 8.6 mo (range, 0.2–60.8 mo); 24% of pts are still on treatment. Dose escalation to BOS 600 mg/d occurred in 19% of pts. Time from last pt's first dose to data cutoff was 25 mo (median follow-up duration of 31.4 mo [range, 0.3–66.0 mo]). A confirmed complete hematologic response (CHR) was attained/maintained by 73% of evaluable pts (Table). The Kaplan-Meier (KM) probability of maintaining a CHR at 2 y was 67%. A major cytogenetic response (MCyR) was attained/maintained by 41%, including 32% with a complete cytogenetic response (CCyR). Among evaluable pts without a baseline CCyR, 36% (n = 37/102) achieved a MCyR, including 28 (28%) with a CCyR. The KM probability of maintaining a MCyR at 2 y was 71%. Of 86 pts with baseline mutation status, 40 (47%) pts had 19 unique Bcr-Abl kinase domain mutations, including 7 (8%) pts with T315I. Responses were seen across mutations (75% CHR, 43% MCyR excluding T315I), including those conferring resistance to other TKIs; responses in pts with T315I were low (29% CHR; 14% MCyR). Nine of 37 pts evaluated at baseline and treatment discontinuation had ≥1 new mutation (V299L, n = 4; L248V, n = 2; T315I, n = 2; F359C, n = 1; G250E, n = 1); 8 of 9 pts had discontinued BOS due to disease progression or lack of efficacy. On-treatment transformation to accelerated phase CML occurred in 5 (4%) pts after 16 to 428 d on study; no pt transformed to blast phase CML. KM-estimated on-treatment progression-free survival (PFS) at 2 y was 75%; KM-estimated overall survival (OS) at 2 y was 84% (Table). There were 23 (19%) deaths on study, with 6 deaths occurring ≤30 d after the last BOS dose. Most deaths were due to disease progression (n = 10 [8%]) or an adverse event (AE; n = 10 [8%]; including 1 treatment-related death due to gastrointestinal bleeding). Three deaths were due to unknown cause ≥509 d after the last BOS dose. Non-hematologic treatment-emergent AEs (TEAEs) seen in ≥20% of pts (all grades; grade 3/4) included diarrhea (82%; 8%), nausea (49%; 1%), vomiting (40%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (24%; 1%), and abdominal pain (20%; 1%). The incidence of individual TEAEs was generally similar across groups regardless of prior TKI exposure. Diarrhea TEAEs were predominantly grade 1/2, first reported early during treatment (median time to first event of 1.5 d [range, 1–210 d]), and transient (median event duration of 2 d [range, 1–524 d]). The incidence of pleural effusion was highest among DAS-intolerant pts (n = 11 [22%], including 3 pts with grade 3 events); for 9 of 11 pts pleural effusion had been indicated as a reason for intolerance to prior DAS. Grade 3/4 laboratory abnormalities reported in ≥10% of pts included thrombocytopenia (25%), neutropenia (19%), lymphopenia (17%), and hypermagnesemia (12%). Dose reductions and interruptions were used to manage AEs in 50% and 66% of pts. A total of 32 (27%) pts discontinued treatment due to an AE, most commonly hematologic events. In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity after follow-up of ≥24 mo in CP CML following resistance or intolerance to multiple TKIs, with a majority of pts maintaining response at 2 y and few new transformations, deaths, TEAEs, or discontinuations due to AEs since the prior report ∼1 y earlier (Blood 2012;119:4303–12). n (%) IM + DAS-R IM + DAS-I IM + NIL-R IM + DAS ± NILa Total Evaluableb 37 49 25 4 115     CHR 23 (62) 39 (80) 19 (76) 3 (75) 84 (73) Evaluableb 36 44 26 4 110     MCyR 12 (33) 21 (48) 10 (39) 2 (50) 45 (41)     CCyR 7 (19) 19 (43) 7 (27) 2 (50) 35 (32) Treated 38 50 27 4 119     PFS at 2 yc 70% 81% 79% 38% 75%     OS at 2 yc 77% 85% 92% 75% 84% R, resistant; I, intolerant. a Includes 3 pts with prior exposure to all 3 TKIs and 1 NIL-I pt. KM rates may be unreliable due to the small number of pts in this cohort. b Received ≥1 dose of BOS and had a valid baseline response assessment. c Based on KM estimates Disclosures: Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Kantarjian:Pfizer: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marin:Novartis: Research Funding; BMS: Research Funding. Dorlhiac-Llacer:Novartis, Bristol Myer Squibb, Pfizer: Research Funding. Bullorsky:Novartis, BMS: Consultancy, Speakers Bureau. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Turnbull:Pfizer Inc, l3/Inventiv Clinical Solutions: Employment. Besson:Pfizer Inc: Employment. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

Acquisition Of Compound BCR-ABL1 Alleles As A Mechanism Of Resistance To Ponatinib In Chronic Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 853-853
Author(s):  
Don L Gibbons ◽  
Sabrina Pricl ◽  
Paola Posocco ◽  
Erik Laurini ◽  
Maurizio Fermeglia ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
In Silico ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Significant Proportion ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
The Impact ◽  
In Cells

Abstract BACKGROUND Ponatinib targets the inactive conformation of the ABL1 kinase and avoids interacting with the side chain of the mutated 315 residue. In vitro, ponatinib inhibits all single-point BCR-ABL1 mutations. Yet, a significant proportion of patients with chronic myeloid leukemia in chronic phase (CML–CP) do not respond to ponatinib and a subset loses their response during the course of treatment. The mechanisms of resistance to ponatinib are currently not well characterized. OBJECTIVE To determine the impact of compound BCR-ABL1 mutations (polymutants) on the activity of ponatinib. METHODS BCR-ABL1 mutational status was determined in 70 pts with CML-CP post imatinib failure and during dasatinib therapy by DNA expansion of specific clones followed by DNA sequencing of ≥10 clones. Free energy of binding (DGbind) for the unmutated and all mutant BCR-ABL1 kinase/inhibitor complexes were obtained using Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) methodology. Single and polymutant BCR-ABL1 alleles obtained by direct mutagenesis and their expression was forced into Ba/F3 cells by electroporation by the pMX/eGFP-BCR-ABL1 expression vector using the Amaxa System. RESULTS After imatinib failure, 125 ABL1 kinase domain mutations at 113 amino acid positions were detected in 61/70 (87%) pts, including 38 (54%) with mutations in ≥20% of sequenced clones. Mutations conferring resistance to >1µM imatinib were detected in 30 (43%) pts. Polymutant BCR-ABL1 alleles were detected in 29/70 (41%) pts. These patients received dasatinib for a median of 19 mos (range, 2-52), during which dasatinib-resistant mutations were detected in 10/32 (31%) assessable cases (5 with T315I). Polymutants were present in 16/32 (50%) pts (all of them dead in blast phase). The proportion of clones carrying unmutated BCR-ABL1 was markedly lower in patients who only achieved a minor or no cytogenetic response compared to those achieving a major cytogenetic response (p=0.0001), suggesting exhaustion of unmutated clones and expansion of mutant (and polymutant) clones linked to clinical dasatinib resistance. Then, we performed 3D structural analyses to determine the thermodynamic impact of 21 BCR-ABL1 mutants (11 single and 10 double mutants) in the ability of ponatinib to bind the kinase domain (Table). Most single mutants did not result in high ponatinib resistance (except for E255K, IC50=8.8nM; DGbind=-10.99±0.01). However, the association of any 2 of 3 point mutants (T315I, F317L, V299L) in a dual polymutant produced highly resistant BCR-ABL1 proteins that exhibited fold change values from 19 to 40, compared to the unmutated protein, with T315I/F359V displaying the highest resistance (IC50=61nM; DGbind=-10.23±0.03 kcal/mol), unveiling a mechanism of escape to ponatinib. In Ba/F3-based assays, ponatinib (but not imatinib or dasatinib) was active against Ba/F3-BCR-ABL1T315I cells. Polymutants exhibited very high ponatinib resistance (10-fold higher than that of cells carrying BCR-ABL1T315I). As predicted in silico, BCR-ABL1T315I/F359V was the most resistant polymutant tested. Cell growth inhibition was coupled with CrkL and STAT5 phosphorylation inhibition. Ponatinib, while suppressing STAT5 phosphorylation, could not suppress CrkL phosphorylation in cells expressing the BCR-ABL1T315I/F359V polymutant kinase, even at 100 nM (50-fold the IC50 required to inhibit BCR-ABL1T315I). CONCLUSIONS Polymutants are very frequent in pt samples after TKI failure (particularly after sequential TKI therapy) and tend to induce high ponatinib resistance. Our in silico platform predicted very accurately TKI sensitivity in cells carrying different BCR-ABL1 mutations, which makes it clinically applicable for matching specific mutations to the most effective TKI. Some polymutants require ponatinib concentrations not clinically reachable, thus representing a mechanism of escape to ponatinib therapy through selection and expansion of refractory clones. Disclosures: Talpaz: ariad: Research Funding. Cortes:Ariad: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding. Quintas-Cardama:ariad: Consultancy.

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